RESUMEN
Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder2,3, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were 'probably' or 'possibly' amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.
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Ataxia Telangiectasia , Empalme del ARN , Niño , Humanos , Ataxia Telangiectasia/tratamiento farmacológico , Ataxia Telangiectasia/genética , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/uso terapéutico , Estudios Prospectivos , Empalme del ARN/efectos de los fármacos , Empalme del ARN/genética , Secuenciación Completa del Genoma , Intrones , Exones , Medicina de Precisión , Proyectos PilotoRESUMEN
T-cell-mediated approaches have shown promise in myeloma treatment. However, there are currently a limited number of specific myeloma antigens that can be targeted, and multiple myeloma (MM) remains an incurable disease. G-protein-coupled receptor class 5 member D (GPRC5D) is expressed in MM and smoldering MM patient plasma cells. Here, we demonstrate that GPRC5D protein is present on the surface of MM cells and describe JNJ-64407564, a GPRC5DxCD3 bispecific antibody that recruits CD3+ T cells to GPRC5D+ MM cells and induces killing of GPRC5D+ cells. In vitro, JNJ-64407564 induced specific cytotoxicity of GPRC5D+ cells with concomitant T-cell activation and also killed plasma cells in MM patient samples ex vivo. JNJ-64407564 can recruit T cells and induce tumor regression in GPRC5D+ MM murine models, which coincide with T-cell infiltration at the tumor site. This antibody is also able to induce cytotoxicity of patient primary MM cells from bone marrow, which is the natural site of this disease. GPRC5D is a promising surface antigen for MM immunotherapy, and JNJ-64407564 is currently being evaluated in a phase 1 clinical trial in patients with relapsed or refractory MM (NCT03399799).
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Anticuerpos Biespecíficos/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Mieloma Múltiple/terapia , Receptores Acoplados a Proteínas G/inmunología , Linfocitos T/efectos de los fármacos , Animales , Anticuerpos Biespecíficos/inmunología , Antineoplásicos Inmunológicos/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Humanos , Inmunoterapia , Ratones Endogámicos BALB C , Mieloma Múltiple/inmunología , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Complete revascularization (CR) of nonculprit lesions (NCL) is strongly recommended in patients with ST-elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD), but no definitive evidence is available regarding which diagnostic strategy should be preferred. Instantaneous wave-free ratio (iFR) has never been investigated in this setting. We aimed to describe clinical outcomes of a cohort of patients undergoing iFR-guided CR. METHODS: Following primary percutaneous coronary intervention (PCI), consecutive patients with STEMI and intermediate NCL were enrolled and destinated to an iFR-guided CR. NCL with iFR ≤ 0.89 underwent PCI while NCL with iFR > 0.89 were deferred. The primary endpoint was NC target lesion failure (NC-TLF) and the secondary endpoint was major adverse cardiovascular events (MACE), at 1-year follow-up. RESULTS: Overall, 209 patients were enrolled (ischemic iFR = 83; nonischemic iFR = 126). Patients with ischemic iFR showed a higher prevalence of traditional cardiovascular risk factors and angiographically determined three-vessel disease. In the entire cohort, NC-TLF and MACE occurred in 6.7% and 10.5% of patients, respectively. Compared to the deferred group, patients with ischemic iFR experienced significantly higher rates of both NC-TLF (3.2% vs. 12.1%; p = 0.021) and MACE (7.1% vs. 16.9%; p = 0.041). These results were mostly driven by increased rates of NC-TLF PCI and further revascularizations in this latter group, while no differences were evident in terms of nonfatal myocardial infarction or death. At multivariable analysis, the strongest predictor of MACE was symptom onset to balloon time (HR = 1.17 [95% CI: 1.04-1.31], p = 0.008). CONCLUSIONS: In our study enrolling STEMI patients with MVD, iFR assessment was feasible and safe. PCI-deferring according to iFR evaluation of NCL was associated with low rates of adverse events. Further randomized studies are needed to investigate the effectiveness of iFR-guided revascularization compared to current practice in this setting.
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Enfermedad de la Arteria Coronaria , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/terapia , Humanos , Intervención Coronaria Percutánea/efectos adversos , Intervención Coronaria Percutánea/métodos , Sistema de Registros , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/terapia , Resultado del TratamientoRESUMEN
Animal flight requires aerodynamic power, which is challenging to determine accurately in vivo Existing methods rely on approximate calculations based on wake flow field measurements, inverse dynamics approaches, or invasive muscle physiological recordings. In contrast, the external mechanical work required for terrestrial locomotion can be determined more directly by using a force platform as an ergometer. Based on an extension of the recent invention of the aerodynamic force platform, we now present a more direct method to determine the in vivo aerodynamic power by taking the dot product of the aerodynamic force vector on the wing with the representative wing velocity vector based on kinematics and morphology. We demonstrate this new method by studying a slowly flying dove, but it can be applied more generally across flying and swimming animals as well as animals that locomote over water surfaces. Finally, our mathematical framework also works for power analyses based on flow field measurements.
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Vuelo Animal , Alas de Animales , Animales , Fenómenos Biomecánicos , Columbidae , Locomoción , Modelos BiológicosRESUMEN
BACKGROUND: Functional assessment of non-infarct-related artery lesions during primary percutaneous coronary intervention (PCI) might be useful to avoid revascularization of nonsignificant stenosis and staged procedures, thus reducing hospital stay. We aimed to assess the diagnostic performance of instantaneous wave-free ratio (iFR) as compared with fractional flow reserve (FFR) in this setting. METHODS: In the WAVE study, a prospective, observational, single-center registry (NCT02869906), paired iFR and FFR measurements were performed at the level of non-IRA lesions in patients with ST-segment elevation myocardial infarction both during primary PCI and during staged procedures (5-8 days after). RESULTS: Paired iFR and FFR measurements were available for 66 non-IRA lesions in 50 patients. The iFR and FFR values of non-IRA lesions did not change significantly between the index and staged procedure. Bland-Altman analysis did not show systematic bias for either iFR or FFR repeated measures. Receiver operating characteristic curve analysis showed high accuracy of iFR to identify positive (≤0.80) FFR measurements in the index procedure with an area under the curve of 0.95. A cutoff of ≤0.89 for iFR in the index procedure had the best combination of sensitivity (95%) and specificity (90%) with positive and negative predictive values of 86% and 97%, respectively. Finally, iFR measured during the index procedure was significantly correlated with FFR (r=0.71, r2=0.51; P<.0001). CONCLUSIONS: The WAVE study shows that iFR yields similar diagnostic accuracy to FFR in functional evaluation of non-IRA stenosis in patients with STEMI and multivessel CAD, with the advantage of being adenosine free.
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Vasos Coronarios/diagnóstico por imagen , Reserva del Flujo Fraccional Miocárdico/fisiología , Infarto del Miocardio con Elevación del ST/fisiopatología , Anciano , Angiografía por Tomografía Computarizada , Angiografía Coronaria , Vasos Coronarios/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Revascularización Miocárdica , Valor Predictivo de las Pruebas , Estudios Prospectivos , Curva ROC , Reproducibilidad de los Resultados , Infarto del Miocardio con Elevación del ST/diagnóstico , Infarto del Miocardio con Elevación del ST/cirugíaRESUMEN
In the elderly mitral regurgitation is very frequent and surgical correction of mitral regurgitation (MR) has often a high operative risk, consequently, over the years, different percutaneous transcatheter techniques have been developed as a valid alternative to surgery. The edge-to-edge repair with the MitraClip device has gained a wide clinical application, supported by several studies, both randomize trials and registries. It is indicated in functional MR as in degenerative MR. The outcome is usually positive, resulting in a reduction of the regurgitation to grade 1+ or 2+ and an improvement in the functional class to I or II reducing hospitalizations. Its cost-effectiveness too is supported by some studies.
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Implantación de Prótesis de Válvulas Cardíacas/métodos , Hospitalización/economía , Insuficiencia de la Válvula Mitral/cirugía , Válvula Mitral/cirugía , Anciano , Análisis Costo-Beneficio , Hospitalización/estadística & datos numéricos , Humanos , Válvula Mitral/patología , Insuficiencia de la Válvula Mitral/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
We describe a 63 year old Romanian female patient admitted to our institution with complaints of typical angina and a diagnosis of non ST-elevation myocardial infarction. Coronary arteriography unveiled anomalous origin of a left circumflex coronary artery from the right coronary sinus of Valsalva near the right coronary ostium and a hyperdominant left anterior descending coronary artery giving off a posterior descending coronary artery with small distal-posterolateral left ventricular branch. The co-existence of a left circumflex coronary artery originating ectopically from the right sinus of Valsalva together with a posterior descending coronary artery originating from the distal end of the anterior descending artery is important to keep in mind especially by those doing coronary angiography in the cardiac catheterization laboratory.
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Seno Coronario/diagnóstico por imagen , Anomalías de los Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/diagnóstico por imagen , Infarto del Miocardio sin Elevación del ST/diagnóstico por imagen , Angiografía Coronaria , Seno Coronario/anomalías , Anomalías de los Vasos Coronarios/complicaciones , Femenino , Humanos , Persona de Mediana Edad , Infarto del Miocardio sin Elevación del ST/complicacionesRESUMEN
More than a million insects and approximately 11,000 vertebrates utilize flapping wings to fly. However, flapping flight has only been studied in a few of these species, so many challenges remain in understanding this form of locomotion. Five key aerodynamic mechanisms have been identified for insect flight. Among these is the leading edge vortex, which is a convergent solution to avoid stall for insects, bats and birds. The roles of the other mechanisms - added mass, clap and fling, rotational circulation and wing-wake interactions - have not yet been thoroughly studied in the context of vertebrate flight. Further challenges to understanding bat and bird flight are posed by the complex, dynamic wing morphologies of these species and the more turbulent airflow generated by their wings compared with that observed during insect flight. Nevertheless, three dimensionless numbers that combine key flow, morphological and kinematic parameters - the Reynolds number, Rossby number and advance ratio - govern flapping wing aerodynamics for both insects and vertebrates. These numbers can thus be used to organize an integrative framework for studying and comparing animal flapping flight. Here, we provide a roadmap for developing such a framework, highlighting the aerodynamic mechanisms that remain to be quantified and compared across species. Ultimately, incorporating complex flight maneuvers, environmental effects and developmental stages into this framework will also be essential to advancing our understanding of the biomechanics, movement ecology and evolution of animal flight.
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Aves/fisiología , Quirópteros/fisiología , Vuelo Animal/fisiología , Insectos/fisiología , Alas de Animales/fisiología , Animales , Fenómenos Biomecánicos , Modelos BiológicosRESUMEN
Avian takeoff requires peak pectoralis muscle power to generate sufficient aerodynamic force during the downstroke. Subsequently, the much smaller supracoracoideus recovers the wing during the upstroke. How the pectoralis work loop is tuned to power flight is unclear. We integrate wingbeat-resolved muscle, kinematic, and aerodynamic recordings in vivo with a new mathematical model to disentangle how the pectoralis muscle overcomes wing inertia and generates aerodynamic force during takeoff in doves. Doves reduce the angle of attack of their wing mid-downstroke to efficiently generate aerodynamic force, resulting in an aerodynamic power dip, that allows transferring excess pectoralis power into tensioning the supracoracoideus tendon to assist the upstroke-improving the pectoralis work loop efficiency simultaneously. Integrating extant bird data, our model shows how the pectoralis of birds with faster wingtip speed need to generate proportionally more power. Finally, birds with disproportionally larger wing inertia need to activate the pectoralis earlier to tune their downstroke.
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Columbidae , Vuelo Animal , Animales , Fenómenos Biomecánicos , Vuelo Animal/fisiología , Alas de Animales/fisiología , Músculos , Modelos BiológicosRESUMEN
Limited data are available about the impact of permanent pacemaker (PPM) implantation on long-term survival in patients with a bicuspid aortic valve (BAV) and severe aortic stenosis (AS) treated with transcatheter aortic valve replacement (TAVR). We aimed to evaluate the long-term clinical outcomes of patients with BAV with AS who underwent periprocedural PPM implantation after TAVR with a self-expandable prosthesis. Data from patients with BAV and severe AS who underwent TAVR between April 2009 and January 2022 and followed in the framework of the One Hospital ClinicalService-CoreValve Project were collected. Patients were categorized in 2 groups according to PPM implantation after TAVR ("PPM" group) or not ("no PPM" group). The coprimary end points were all-cause death and a composite of cardiac mortality, rehospitalization because of cardiac causes, stroke, and myocardial infarction. Overall, 106 patients were considered (74 in the "no PPM" group and 32 in the "PPM" group). No statistically significant difference was found between the groups in terms of follow-up and baseline characteristics. Patients in the PPM group were more likely to show baseline conduction abnormalities (p = 0.023). Patients in the PPM group were more often treated with older generation prosthesis than those in the no PPM group (28.1% vs 5.4%, respectively, p = 0.013). At 2 years of follow-up, all-cause death in the no PPM and PPM groups occurred in 20.0% and 10.0% of patients, respectively (hazard ratio 0.37, 95% confidence interval 0.08 to 1.67). Similarly, no difference was evident for the composite end point between the 2 groups (no PPM vs PPM: 8 [14.6%] vs 6 [19.3%], hazard ratio 1.67, 95% CI 0.58 to 4.81). In conclusion, patients with severe AS and BAV treated with TAVR complicated by PPM implantation are not exposed to an increased risk of major adverse events at 2 years of follow-up.
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Estenosis de la Válvula Aórtica , Enfermedad de la Válvula Aórtica Bicúspide , Marcapaso Artificial , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Enfermedad de la Válvula Aórtica Bicúspide/cirugía , Resultado del Tratamiento , Válvula Aórtica/cirugía , Factores de RiesgoRESUMEN
Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.
RESUMEN
The metastasis-invasion cascade describes the series of steps required for a cancer cell to successfully spread from its primary tumor and ultimately grow within a secondary organ. Despite metastasis being a dynamic, multistep process, most omics studies to date have focused on comparing primary tumors to the metastatic deposits that define end-stage disease. This static approach means we lack information about the genomic and epigenomic changes that occur during the majority of tumor progression. One particularly understudied phase of tumor progression is metastatic colonization, during which cells must adapt to the new microenvironment of the secondary organ. Through temporal profiling of chromatin accessibility and gene expression in vivo, we identify dynamic changes in the epigenome that occur as osteosarcoma tumors form and grow within the lung microenvironment. Furthermore, we show through paired in vivo and in vitro CRISPR drop-out screens and pharmacological validation that the upstream transcription factors represent a class of metastasis-specific dependency genes. While current models depict lung colonization as a discrete step within the metastatic cascade, our study shows it is a defined trajectory through multiple epigenetic states, revealing new therapeutic opportunities undetectable with standard approaches.
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Neoplasias Óseas , Osteosarcoma , Humanos , Cromatina/genética , Osteosarcoma/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Epigenoma , Neoplasias Óseas/genética , Microambiente TumoralRESUMEN
Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by a translocation that creates the chimeric transcription factor PAX3-FOXO1 (P3F), which assembles de novo super enhancers to drive high levels of transcription of other core regulatory transcription factors (CRTFs). P3F recruits co-regulatory factors to super enhancers such as BRD4, which recognizes acetylated lysines via BET bromodomains. In this study, we demonstrate that inhibition or degradation of BRD4 leads to global decreases in transcription, and selective downregulation of CRTFs. We also show that the BRD4 degrader ARV-771 halts transcription while preserving RNA Polymerase II (Pol2) loops between super enhancers and their target genes, and causes the removal of Pol2 only past the transcriptional end site of CRTF genes, suggesting a novel effect of BRD4 on Pol2 looping. We finally test the most potent molecule, inhibitor BMS-986158, in an orthotopic PDX mouse model of FP-RMS with additional high-risk mutations, and find that it is well tolerated in vivo and leads to an average decrease in tumor size. This effort represents a partnership with an FP-RMS patient and family advocates to make preclinical data rapidly accessible to the family, and to generate data to inform future patients who develop this disease.
RESUMEN
Activation of oncogenic gene expression from long-range enhancers is initiated by the assembly of DNA-binding transcription factors (TF), leading to recruitment of co-activators such as CBP/p300 to modify the local genomic context and facilitate RNA-Polymerase 2 (Pol2) binding. Yet, most TF-to-coactivator recruitment relationships remain unmapped. Here, studying the oncogenic fusion TF PAX3-FOXO1 (P3F) from alveolar rhabdomyosarcoma (aRMS), we show that a single cysteine in the activation domain (AD) of P3F is important for a small alpha helical coil that recruits CBP/p300 to chromatin. P3F driven transcription requires both this single cysteine and CBP/p300. Mutants of the cysteine reduce aRMS cell proliferation and induce cellular differentiation. Furthermore, we discover a profound dependence on CBP/p300 for clustering of Pol2 loops that connect P3F to its target genes. In the absence of CBP/p300, Pol2 long range enhancer loops collapse, Pol2 accumulates in CpG islands and fails to exit the gene body. These results reveal a potential novel axis for therapeutic interference with P3F in aRMS and clarify the molecular relationship of P3F and CBP/p300 in sustaining active Pol2 clusters essential for oncogenic transcription.
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ARN Polimerasa II , Rabdomiosarcoma Alveolar , Humanos , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , Cisteína/metabolismo , Factores de Transcripción/metabolismo , Factor de Transcripción PAX3/genética , Rabdomiosarcoma Alveolar/genética , ARN/metabolismo , Activación Transcripcional , Unión Proteica , Proteína Forkhead Box O1/metabolismoRESUMEN
Birds frequently manoeuvre around plant clutter in complex-structured habitats. To understand how they rapidly negotiate obstacles while flying between branches, we measured how foraging Pacific parrotlets avoid horizontal strings obstructing their preferred flight path. Informed by visual cues, the birds redirect forces with their legs and wings to manoeuvre around the obstacle and make a controlled collision with the goal perch. The birds accomplish aerodynamic force vectoring by adjusting their body pitch, stroke plane angle and lift-to-drag ratios beat-by-beat, resulting in a range of about 100° relative to the horizontal plane. The key role of drag in force vectoring revises earlier ideas on how the avian stroke plane and body angle correspond to aerodynamic force direction-providing new mechanistic insight into avian manoeuvring-and how the evolution of flight may have relied on harnessing drag.
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Vuelo Animal , Alas de Animales , Animales , Fenómenos Biomecánicos , Aves , Fenómenos MecánicosRESUMEN
Legacy mining facilities pose significant risks to aquatic resources. From March 30th to April 9th, 2021, 814 million liters of phosphate mining wastewater and marine dredge water from the Piney Point facility were released into lower Tampa Bay (Florida, USA). This resulted in an estimated addition of 186 metric tons of total nitrogen, exceeding typical annual external nitrogen load estimates to lower Tampa Bay in a matter of days. An initial phytoplankton bloom (non-harmful diatoms) was first observed in April. Filamentous cyanobacteria blooms (Dapis spp.) peaked in June, followed by a bloom of the red tide organism Karenia brevis. Reported fish kills tracked K. brevis concentrations, prompting cleanup of over 1600 metric tons of dead fish. Seagrasses had minimal changes over the study period. By comparing these results to baseline environmental monitoring data, we demonstrate adverse water quality changes in response to abnormally high and rapidly delivered nitrogen loads.
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Bahías , Cianobacterias , Contaminación del Agua , Animales , Florida , Floraciones de Algas Nocivas , Minería , Nitrógeno/análisis , NutrientesRESUMEN
OBJECTIVES: To evaluate the short- and long-term clinical and echocardiographic outcomes of the percutaneous closure of the patent foramen ovale (PFO) with an atrial septal aneurysm (ASA) using 2 different devices. METHODS: We enrolled 100 patients with PFO and ASA. Fifty consecutive patients had transcatheter closure of the PFO with the Gore Cardioform septal occluder (GSO) (Gore Medical) and a second group of 50 consecutive patients with the Amplatzer PFO occluder (APO) (Abbott). A clinical and transthoracic echocardiographic follow-up was performed at 1, 3, 6, and 12 months after the implant procedure. The primary endpoint was the incidence of moderate-to-severe residual right-to-left shunting (rRLS) at the 6-month follow-up. The procedural results and the recurrence of embolic events at 1 year were also investigated. RESULTS: The procedure was successful in all patients. The immediate postprocedural moderate-to-severe rRLS incidence was similar between the 2 groups (GSO 14% vs APO 12%; P=NS) as well as the incidence of moderate-to-severe rRLS at the 6-month follow-up (GSO 4% vs APO 4%; P=non-significant). In only 1 patient of the GSO group, there was a persistent moderate rRLS at the 1-year follow-up. The 6-month and 1-year complete occlusion rate for all subjects was 93% and 96%, respectively. No devices embolized and no death or recurrent embolic events were observed during hospitalization through the 1-year follow-up. CONCLUSIONS: GSO and APO devices appear to be safe and effective devices for the percutaneous closure of a PFO with ASA, showing similar results for the presence of rRLS at the 6-month follow-up, complete occlusion rate, and clinical embolic recurrences.
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Foramen Oval Permeable , Aneurisma Cardíaco , Dispositivo Oclusor Septal , Cateterismo Cardíaco , Ecocardiografía , Estudios de Seguimiento , Foramen Oval Permeable/complicaciones , Foramen Oval Permeable/diagnóstico , Foramen Oval Permeable/cirugía , Aneurisma Cardíaco/diagnóstico , Aneurisma Cardíaco/etiología , Aneurisma Cardíaco/cirugía , Humanos , Resultado del TratamientoRESUMEN
How hummingbirds hum is not fully understood, but its biophysical origin is encoded in the acoustic nearfield. Hence, we studied six freely hovering Anna's hummingbirds, performing acoustic nearfield holography using a 2176 microphone array in vivo, while also directly measuring the 3D aerodynamic forces using a new aerodynamic force platform. We corroborate the acoustic measurements by developing an idealized acoustic model that integrates the aerodynamic forces with wing kinematics, which shows how the timbre of the hummingbird's hum arises from the oscillating lift and drag forces on each wing. Comparing birds and insects, we find that the characteristic humming timbre and radiated power of their flapping wings originates from the higher harmonics in the aerodynamic forces that support their bodyweight. Our model analysis across insects and birds shows that allometric deviation makes larger birds quieter and elongated flies louder, while also clarifying complex bioacoustic behavior.
Anyone walking outdoors has heard the whooshing sound of birdwings flapping overhead, the buzzing sound of bees flying by, or the whining of mosquitos seeking blood. All animals with flapping wings make these sounds, but the hummingbird makes perhaps the most delightful sound of all: their namesake hum. Yet, how hummingbirds hum is poorly understood. Bird wings generate large vortices of air to boost their lift and hover in the air that can generate tones. Further, the airflow over bird wings can be highly turbulent, meaning it can generate loud sounds, like the jets of air coming out of the engines of aircraft. Given all the sound-generating mechanisms at hand, it is difficult to determine why some wings buzz whereas others whoosh or hum. Hightower, Wijnings et al. wanted to understand the physical mechanism that causes animal wings to whine, buzz, hum or whoosh in flight. They hypothesized that the aerodynamic forces generated by animal wings are the main source of their characteristic wing sounds. Hummingbird wings have the most features in common with different animals' wings, while also featuring acoustically complex feathers. This makes them ideal models for deciphering how birds, bats and even insects make wing sounds. To learn more about wing sounds, Hightower, Wijnings et al. studied how a species of hummingbird called Anna's hummingbird hums while drinking nectar from a flower. A three-dimensional 'acoustic hologram' was generated using 2,176 microphones to measure the humming sound from all directions. In a follow-up experiment, the aerodynamic forces the hummingbird wings generate to hover were also measured. Their wingbeat was filmed simultaneously in slow-motion in both experiments. Hightower, Wijnings et al. then used a mathematical model that governs the wing's aeroacoustics to confirm that the aerodynamic forces generated by the hummingbirds' wings cause the humming sound heard when they hover in front of a flower. The model shows that the oscillating aerodynamic forces generate harmonics, which give the wings' hum the acoustic quality of a musical instrument. Using this model Hightower, Wijnings et al. found that the differences in the aerodynamic forces generated by bird and insect wings cause the characteristic timbres of their whines, buzzes, hums, or whooshes. They also determined how these sounds scale with body mass and flapping frequency across 170 insect species and 80 bird species. This showed that mosquitos are unusually loud for their body size due to the unusual unsteadiness of the aerodynamic forces they generate in flight. These results explain why flying animals' wings sound the way they do for example, why larger birds are quieter and mosquitos louder. Better understanding of how the complex forces generated by animal wings create sound can advance the study of how animals change their wingbeat to communicate. Further, the model that explains how complex aerodynamic forces cause sound can help make the sounds of aerial robots, drones, and fans not only more silent, but perhaps more pleasing, like the hum of a hummingbird.
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Aves/fisiología , Vuelo Animal , Sonido , Alas de Animales/fisiología , Animales , Fenómenos Biomecánicos , Alas de Animales/anatomía & histologíaRESUMEN
Several naphthalene Unit Risk Factors (URFs) were proposed by the US Environmental Protection Agency in 2004 using data on the development of olfactory epithelial neuroblastomas and nasal respiratory epithelial adenomas in rats, but these URFs may be inappropriate and unnecessarily conservative for estimating human cancer risks. The purpose of the present exercise was to perform a screening-level population risk assessment of the US population to compare the observed number of naphthalene-induced nasal tumors in the US to the number that would be predicted if the URFs for naphthalene were as proposed. Nine scenarios were evaluated to represent the range of exposures individuals have typically experienced. Results indicate that the total predicted burden of naphthalene-induced nasal tumors per year in the US (65,905 rare nasal tumors, of which 29,121 are olfactory epithelial neuroblastomas) is much greater than the number of these tumors actually observed per year (910 total nasal tumors, of which 66 are olfactory neuroblastomas) over the period 1973-2006. This suggests that using rat nasal tumor data to derive a naphthalene URF for humans should be re-evaluated.
Asunto(s)
Estesioneuroblastoma Olfatorio/inducido químicamente , Exposición por Inhalación/efectos adversos , Naftalenos/toxicidad , Cavidad Nasal , Neoplasias Nasales/inducido químicamente , Contaminación del Aire Interior/efectos adversos , Contaminación del Aire Interior/análisis , Bases de Datos Factuales , Estesioneuroblastoma Olfatorio/epidemiología , Humanos , Exposición por Inhalación/análisis , Neoplasias Nasales/epidemiología , Exposición Profesional/efectos adversos , Exposición Profesional/análisis , Pronóstico , Medición de Riesgo , Estados Unidos/epidemiologíaRESUMEN
INTRODUCTION: Rehabilitation post-stroke is critical for maximizing patient outcomes. This study assessed the feasibility of implementing and evaluating a continuing professional development (CPD) intervention aimed at increasing the uptake of stroke best practice guidelines among physiotherapists (PTs), occupational therapists (OTs) and speech-language pathologists (SLPs) in six university-affiliated stroke rehabilitation centers in Quebec, Canada. METHOD: Twelve stroke best practice recommendations with reflective tools were sent weekly by e-mail. Participants' eligibility criteria included: a) profession; b) practicing more than 1 year in a stroke rehabilitation program; c) fluency in French or English; and d) basic computer literacy. Feasibility (operationalized via participation, satisfaction and relevance), cognitive impact, perceived application in practice and expected patient outcomes were measured over 24 weeks using three questionnaires and analyzed using descriptive statistics. RESULTS: The sample totaled 62 of 133 eligible (47%) clinicians. Satisfaction, relevance and cognitive impact of delivered information varied across disciplines and recommendations. Agreement with the recommendations was high across disciplines. On average, three-interdisciplinary recommendations (related to post-stoke depression, post-stoke fatigue and patients' and caregivers' learning needs) were rated as the most relevant for at least one patient. The majority of clinicians would use the recommendations for a specific patient and expected health benefits by applying those recommendations. CONCLUSION: This study demonstrated the feasibility of assessing the impact of a CPD intervention in stroke rehabilitation uptake and informed the design of a research program aimed at increasing the use of stroke evidence-based rehabilitation interventions.